Insulin receptor (IR) is a tyrosine kinase receptor, and is a transmembrane receptor that is activated by insulin, IGF-1 or IGF-2. It is a tetramer structure in which 2 α chains (719 residues) comprising insulin-binding portion and 2 β chains (620 residues) comprising membrane penetrating portion are connected by S—S bond. When insulin binds to the receptor, the activity of the tyrosine kinase in the intracellular region of β chains becomes active and phosphorylation of tyrosine residues of receptor occurs. This autophosphorylation causes phosphorylation of other proteins.
Activation of the insulin receptor leads to glucose uptake, and the glucose uptake is inhibited when signaling of the insulin receptor is decreased, leading to secondary diabetes or related complications and hyperglycemia, etc.
Aptamer is a material which consists of 4 kinds of nucleic acids and shows specificity to the target protein according to the combination of the sequence, unlike an antibody consisting of a peptide. The aptamer specific to the target protein is produced in a test tube through SELEX (Systematic Evolution of Ligands by Exponential enrichment), and the process includes a process of finding the aptamer specifically binding to a purified protein in the random combination of pool of aptamer and amplifying it through PCR. A representative single-stranded DNA aptamer new drug, Pegaptanib is an anticancer drug that inhibits vascular epidermal growth factor binding to a vascular epidermal growth factor receptor, used for the vascular epidermal growth factor, and is approved by FDA for clinical use.
Currently, most efforts to identify functional aptamers are focused on the inhibiting ability of aptamer to the target. In particular, a variety of inhibitory aptamers have been developed for treatment of diseases, which interfere with the activity of the target molecule for clinical applications (e.g Macgen, AS1411). However, considering that intermolecular interactions are necessarily accompanied by structural changes, it is believed that activation of protein function will be possible, if aptamer-protein bond can induce a proper structural change of protein. Thus, theoretically, the aptamer has the potential to act as a functional agonist by mimicking specific protein-protein bond. However, the development of the agonist aptamer which activates functions of target remains a difficult problem at present.
In addition, in order to regulate blood sugar of patient normally, many kinds of insulin derivatives have been developed and used in these days, but insulin induces cell division in addition to glucose uptake, and the change of amino acid sequence introduced in some insulin derivatives increases binding to IGF-1 receptor and activation. Thus, the long-term administration of insulin for treating diabetes may increase incidence of cancer and there is a continuing concern about side effects caused by insulin such as atherosclerosis. In addition, it has been reported that there is a significant correlation between persistent administration of insulin and increased incidence of cancer through some epidemiological investigations. Therefore, the development of a biased agonist for insulin receptor which does not induce cell division and only increases glucose uptake will provide a good alternative to insulin administration.
Thus, there is a demand for development of an aptamer which specifically binds to insulin receptor and technology for treating or diagnosing diabetes using thereof.